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J. Biol. Chem., Vol. 280, Issue 20, 19966-19976, May 20, 2005

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Patterns of Gene Expression Differentially Regulated by Platelet-derived Growth Factor and Hypertrophic Stimuli in Vascular Smooth Muscle Cells

MARKERS FOR PHENOTYPIC MODULATION AND RESPONSE TO INJURY^*

Nihal Kaplan-Albuquerque, Yolanda E. Bogaert, Vicki Van Putten, Mary C. Weiser-Evans, and Raphael A. Nemenoff

From the Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262

In vascular smooth muscle cells (VSMC), platelet-derived growth factor (PDGF) suppresses expression of multiple smooth muscle contractile proteins, useful markers of differentiation. Conversely, hypertrophic agents induce expression of these genes. The goal of this study was to employ genomic approaches to identify classes of genes differentially regulated by PDGF and hypertrophic stimuli. Changes in gene expression were determined using Affymetrix RAE-230 GeneChips in rat aortic VSMC stimulated with PDGF. For comparison with a model hypertrophic stimulus, a microarray was performed with VSMC stably expressing constitutively active G₁₆, which strongly induces smooth muscle marker expression. We identified 75 genes whose expression was increased by exposure to PDGF and decreased by expression of G₁₆ and 97 genes whose expression was decreased by PDGF and increased by G₁₆. These genes included many smooth muscle-specific proteins; several extracellular matrix, cytoskeletal, and chemotaxis-related proteins; cell signaling molecules; and transcription factors. Changes in gene expression for many of these were confirmed by PCR or immunoblotting. The contribution of signaling pathways activated by PDGF to the gene expression profile was examined in VSMC stably expressing gain-of-function H-Ras or myristoylated Akt. Among the genes that were confirmed to be differentially regulated were CCAAT/enhancer-binding protein , versican, and nexilin. All of these genes also had altered expression in injured aortas, consistent with a role for PDGF in the response of injured VSMC. These data indicate that genes that are differentially regulated by PDGF and hypertrophic stimuli may represent families of genes and potentially be biomarkers for vascular injury.

Received for publication, January 25, 2005 , and in revised form, March 9, 2005.

^* This work was supported by National Institutes of Health Grants DK 19928 and CA103618. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains four additional tables.

To whom correspondence should be addressed: Division of Renal Diseases and Hypertension, Dept. of Medicine, University of Colorado Health Sciences Center, Box C-281, 4200 E. 9th Ave., Denver, CO 80262. Tel.: 303-315-6733; Fax: 303-315-4852; E-mail: Raphael.Nemenoff{at}UCHSC.edu.

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